Hydrogels are typically described as hydrophilic polymer networks that are capable of absorbing large amounts of water, yet are themselves insoluble because of the presence of physical or chemical crosslinks, entanglements or crystalline regions. Hydrogels have found extensive use in biomedical applications, including as coatings and drug delivery systems. Hydrogels are often sensitive to the conditions of their surrounding environment, such that the swelling ratio of the materials can be affected by temperature, pH, ionic strength and/or the presence of a swelling agent. Several parameters can be used to define or characterize hydrogels, including the swelling ratio under changing conditions, the permeability coefficient of certain solutes, and the mechanical behavior of the hydrogel under conditions of its intended use. When used as drug delivery systems these changes in the environment can often be controlled or predicted in order to regulate drug release. (See Bell and Peppas, cited below).
A particular type of hydrogel that has been described in recent years involves the combination of poly(methacrylic acid) (“PMAA”) backbones and polyethylene glycol (“PEG”) grafts. For instance, Mathur, et al., J. Controlled Release 54(2):177-184 (1998) describe “responsive” hydrogel networks of this type. The hydrogels exhibit swelling transitions, in various solvent systems, and in response to external stimuli. These transitions, in turn, can lead to the formation or disruption of hydrogen-bonded complexes between the backbone and graft portions. The article describes the role of hydrophobic interactions in stabilizing the complexes.
A variety of references further describe the preparation and use of hydrogels for the delivery of medicaments, including those hydrogels based on the combination of polyalkylene glycols and poly(meth)acrylates. See, for instance, U.S. Pat. Nos. 5,884,039 and 5,739,210, which describe polymers having reversible hydrophobic functionalities, e.g., polymers having Lewis acid and Lewis base segments. The segments are hydrophilic and will either swell or dissolve in water. When incorporated into a polymer, the segments form water-insoluble or hydrophobic complexes. Upon changes in pH, temperature or solvent type, the complexes can dissociate, giving large transitions in viscosity, emulsification ability and mechanical strength. The polymers are said to be useful as reversible emulsifiers, super-absorbing resins, or as coatings for pharmaceutical agents.
See also, Scott, et al., Biomaterials 20(15):1371-1380 (1999), which describes the preparation of ionizable polymer networks prepared from oligo(ethylene glycol) multiacrylates and acrylic acid using bulk photopolymerization techniques. The networks are described for use in the preparation of controlled release devices for solutes.
Finally, C. L. Bell, and N. A. Peppas, J. Biomater. Sci. Polymer Edn. 7(8):671-683 (1996) and C. L. Bell and N. A. Peppas, Biomaterials 17:1203-1218 (1996) each describe the synthesis and properties of grafted P(MAA-g-EG) copolymers. The copolymers permit the reversible formation of complexes under appropriate conditions due to hydrogen bonding between the carboxylic acid groups of the PMAA and the oxygen atoms of the PEG chains, resulting in pH-sensitive swelling behavior. Complexation occurs at low pH, resulting in increased hydrophobicity in the polymer network. At higher pH values, the acid groups become ionized and the hydrogen bonding breaks down. The papers studied this pH sensitive swelling behavior in relation to the use of such materials in controlled release drug delivery and bioseparations.
The Bell and Peppas papers exemplified the swelling behavior of P(MAA-g-EG) samples containing 40:60, 50:50 and 60:40 ratios (weight percent) of PMAA:PEG, using PEG grafts having molecular weights of 200, 400 and 1000. The resultant hydrogels were evaluated by several means, including mechanical testing to determine shear modulus. The authors found that as the molecular weight of the PEG graft was increased, the modulus of the networks decreased in both the complexed and uncomplexed state.
When used for drug delivery, the materials prepared by Bell and Peppas were typically used as free standing hydrogel membranes, with no mention of their use upon a surface, let alone the surface of an implanted medical device. Nor, in turn, do these references provide any suggestion of the manner in which such matricies might be applied to any such surface.
Those references that do describe the delivery of medicaments from implanted devices tend to rely on approaches quite different from implanted hydrogels. The continuing development and use of implantable medical devices has led to the corresponding development of a variety of ways to deliver antibiotics and/or antiseptics to the implant site, in order to prevent potential infections associated with such devices.
For instance, a significant percent of fracture fixation devices (pins, nails, screws, etc.) and orthopedic joint implants become infected. Cure of infected orthopedic implants, such as joint prostheses, usually requires both removal of the prosthesis and administration of a long course of antibiotics. In most cases, this is followed by re-implantation of a new joint prosthesis weeks or months later, after making sure that the infection has been eradicated.
As described in the patents to Darouiche, cited below, considerable amount of attention and study has therefore been directed toward preventing colonization of bacterial and fungal organisms on the surfaces of orthopedic implants by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. The objective of such attempts has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization.
Various methods have previously been employed to coat the surfaces of medical devices with an antibiotic. For example, one method involves applying or absorbing to the surface of the medical device a layer of surfactant, such as tridodecylmethyl ammonium chloride (“TDMAC”) followed by an antibiotic coating layer.
A further method known to coat the surface of medical devices with antibiotics involves first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antibiotic composition. See, e.g., Solomon, D. D. and Sheretz, R. J., J. Controlled Release, 6:343-352 (1987) and U.S. Pat. No. 4,442,133. Yet other methods of coating surfaces of medical devices with antibiotics are taught in U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pK of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917,686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ionically bind antibiotics); U.S. Pat. No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); and U.S. Pat. No. 4,952,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders).
See also Ding et al., (U.S. Pat. No. 6,042,875), which describes a coating that permits timed or prolonged pharmacological activity on the surface of medical devices through a reservoir concept. Specifically, the coating comprises at least two layers: an outer layer containing at least one drug-ionic surfactant complex overlying a reservoir layer or tie layer containing a polymer and the drug which is substantially free of an ionic surfactant. Upon exposure to body tissue of a medical device covered with such coating, the ionically complexed drug in the outer layer is released into body fluid or tissue. Following release of such complexed drug, the ionic surfactant complex sites in the outer layer are left vacant.
After insertion of a medical device such as an orthopedic implant, the antibiotics and/or antiseptics quickly leach from the surface of the device into the surrounding environment. Over a relatively short period of time, the amount of antibiotics and/or antiseptics present on the surface decreases to a point where the protection against bacterial and fungal organisms is no longer effective. Furthermore, during implantation of orthopedic fracture fixation devices, such as intramedullary nails and external fixation pins, much of the antimicrobial coating sloughs off due to grating of the coated implant against the bone during insertion of the implant.
Hence, for some implants, and particularly those that both remain in the body for extended periods of time and that undergo tortuous processing in the course of their implantation or use, medicament coatings continue to be sought to provide improved durability.
U.S. Pat. No. 5,853,745 (Darouiche), describes a durable antimicrobial coated orthopedic device or other medical implant having a durable material layer that decreases the rate of leaching of antimicrobial agents into the surrounding environment. The patent provides an antimicrobial coated medical implant or orthopedic device having mechanical resiliency to minimize or avoid sloughing of the antimicrobial layer from the device during insertion. The medical implant has one or more of its surfaces coated with a composition comprising an antimicrobial coating layer comprising an antimicrobial agent in an effective concentration to inhibit the growth of bacterial and fungal organisms, and a protective coating layer formed over said antimicrobial coating layer.
When used as drug release coatings on devices, however, the various systems described above suffer from several drawbacks, e.g., in terms of the thickness of the coatings necessary to provide suitable amounts of drug, the kinetics (e.g., overall period of release), and the durability or tenacity of the coating itself. In spite of the various attempts and progress made to date, it remains clear that the need for a coating composition that provides an optimal combination of such properties as coating thickness, drug release profile, durability, swellability, generic applicability, and surface independence remains unmet.
Improved coatings for use on implanted devices, in order to provide medicament release in situ, are clearly needed.